EP0071738A1 - Theophylline derivatives and process for their preparation - Google Patents

Theophylline derivatives and process for their preparation Download PDF

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EP0071738A1
EP0071738A1 EP82105665A EP82105665A EP0071738A1 EP 0071738 A1 EP0071738 A1 EP 0071738A1 EP 82105665 A EP82105665 A EP 82105665A EP 82105665 A EP82105665 A EP 82105665A EP 0071738 A1 EP0071738 A1 EP 0071738A1
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theophylline
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group
halogen
derivatives
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EP0071738B1 (en
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Kurt Dr. Thiele
Felix Geissmann
Ludwig Dr. Zirngibl
Ulrich Dr. Jahn
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Siegfried AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the reaction can be carried out at elevated temperature with or without the use of a solvent (such as isopropanol).
  • a solvent such as isopropanol
  • the starting materials are kept at the temperature of the mixed melt until periodically taken samples of the reaction mixture, when checked by means of thin-layer chromatography, show that the reaction is essentially complete. It is advantageous to use a proton acceptor to bind the hydrogen halide which is split off, for which the base of the formula (III) used as the starting material can also be used in a 2 to 3-fold excess.
  • the starting materials of the formula (II) are known and the majority are commercially available; if desired, they can be obtained in a known manner (see Medic. Forsch. 27, 5 ff. (1977)) by condensation of theophylline with corresponding alkylene dihalides or epichlorohydrin.
  • the bases of the formula (III) which are used as starting materials are likewise available as commercial products in the form of their hydrochloride salts, from which they are to be released in a manner known to the person skilled in the art before being used for the reaction according to the invention, for example by treatment with alkali metal hydroxide.
  • Th means the theophyllinyl group which is attached in the 7-position to the partial structure shown in the respective example.
  • the 7- (2-chloroethyl) theophylline used as starting material is known and can be obtained by reacting theophylline and ethylene dichloride.
  • the 4- (p-tolyloxy) piperidine used as the free base can be obtained from the corresponding hydrochloride by treatment with sodium hydroxide solution.
  • the residue separated off by filtration is washed twice with water and ethyl acetate, then covered with ethyl acetate and mixed with 100 ml of 2N sodium hydroxide solution. After shaking and phase separation, the majority of the product is in the organic phase; to obtain further amounts of product, the aqueous phase is shaken out twice with 100 ml of ethyl acetate.
  • the combined organic phases are washed with saturated NaCl solution, treated with activated carbon, dried over MgSO 4 and filtered. 20.4 g (80%) of crude crystalline product are obtained from the filtrate by distilling off the solvent.
  • the residue is suspended in 250 ml of carbon tetrachloride and heated to the reflux temperature. The resulting dark brown solution becomes light orange after treatment with activated carbon and supplies 14.5 g of white product with a melting point of 143-145 ° C, which turns out to be pure in the thin-layer chromatogram.
  • the 7- (3-chloropropyl) theophylline used as the starting product can be obtained in a known manner, for example by reacting theophylline with 1,3-bromochloropropane.
  • the aqueous phase is made alkaline by adding concentrated sodium hydroxide solution and extracted twice with ethyl acetate. After recrystallization from chloroform + ethanol (9: 1) and drying in a high vacuum, the substance which crystallizes from the extract shows a melting point of 132-138 ° C.
  • the 7- (3-chloro-2-hydroxypropyl) theophylline used as the starting material can be obtained in a known manner by reacting theophylline with epichlorohydrin.

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Abstract

New derivatives of theophylline having the formula <IMAGE> (I) in which R denotes hydrogen or OH, n the numbers 0 or 1, X either >CH- or >N-, Y either -O- or -CO- and R a five membered or six membered aryl ring or hetero-aryl ring, that is substituted in given cases with halogen, short chain alkyl groups, alkoxy groups or halogen-alkyl, and exhibit in addition to other properties, histamine-, serotinine- bradykynine- antagonistic, anti-anaphylactic and -adrenergic stimulating effects.

Description

Die Erfindung betrifft neue Theophyllinderivate der Formel

Figure imgb0001
und ihrer Salze mit pharmazeutisch zulässigen Säuren. In dieser Formel bedeuten

  • R Wasserstoff oder die Hydroxygruppe
  • n die Zahlen null oder eins
  • X
    Figure imgb0002
  • Y
    Figure imgb0003
    und
  • Ar einen gegebenenfalls mit Niederalkyl oder Niederalkoxy von 1 bis 3 C-Atomen, vorzugsweise Methyl, mit Halogen, insbesondere Fluor, Chlor oder Brom, vorzugsweise Fluor, oder mit Halogenmethyl wie beispielsweise Trifluormethyl substituierten fünf- oder sechsgliedrigen carbocyclischen oder heterocyclischen aromatisch ungesättigten Ring bedeutet, und zwar insbesondere Phenyl, Pyridyl, Furyl, Thienyl, Pyrrolyl oder Imidazolyl, vorzugsweise Phenyl oder Furyl.
The invention relates to new theophyllin derivatives of the formula
Figure imgb0001
 and their salts with pharmaceutically acceptable acids. Mean in this formula
  • R is hydrogen or the hydroxy group
  • n the numbers zero or one
  • X
    Figure imgb0002
  • Y
    Figure imgb0003
     and
  • Ar is a five- or six-membered carbocyclic or heterocyclic aromatic-unsaturated ring which is optionally substituted with lower alkyl or lower alkoxy of 1 to 3 carbon atoms, preferably methyl, with halogen, in particular fluorine, chlorine or bromine, preferably fluorine, or with halogenomethyl such as trifluoromethyl, in particular phenyl, pyridyl, furyl, thienyl, pyrrolyl or imidazolyl, preferably phenyl or furyl.

Diese Verbindungen sind erhältlich nach dem ebenfalls Gegenstand der Erfindung bildenden Verfahren, welches dadurch gekennzeichnet ist, dass man in 7.-Stellung mit einer Gruppe der Formel

Figure imgb0004
substituiertes Theophyllin (wobei R und n die oben genannte Bedeutung haben und "Hal" Chlor oder Brom bedeutet) mit einer Base der Formel
Figure imgb0005
zur Reaktion bringt.These compounds are obtainable by the process which also forms the subject of the invention, which is characterized in that in the 7th position with a group of the formula
Figure imgb0004
 substituted theophylline (where R and n have the meaning given above and "Hal" means chlorine or bromine) with a base of the formula
Figure imgb0005
 to react.

Die Reaktion kann bei erhöhter Temperatur mit oder ohne Verwendung eines Lösungsmittels (wie z.B. Isopropanol) herbeigeführt werden. Beim Arbeiten ohne Lösungsmittel werden die Ausgangsstoffe so lange auf der Temperatur der Mischschmelze gehalten, bis periodisch entnommene Proben des Reaktionsgemisches bei Kontrolle mittels Dünnschicht-Chromatographie erkennen lassen, dass die Reaktion im wesentlichen abgeschlossen ist. Mit Vorteil benützt man dabei zur Bindung des abgespaltenen Halogenwasserstoffes einen Protonenakzeptor, wofür man auch die als Ausgangsstoff benützte Base der Formel (III) in etwa 2- bis 3-fachem Ueberschuss einsetzen kann.The reaction can be carried out at elevated temperature with or without the use of a solvent (such as isopropanol). When working without a solvent, the starting materials are kept at the temperature of the mixed melt until periodically taken samples of the reaction mixture, when checked by means of thin-layer chromatography, show that the reaction is essentially complete. It is advantageous to use a proton acceptor to bind the hydrogen halide which is split off, for which the base of the formula (III) used as the starting material can also be used in a 2 to 3-fold excess.

Die Ausgangsstoffe der Formel (II) sind bekannt und grösstenteils im Handel erhältlich; gewünschtenfalls können sie auf bekanntem Wege (vgl. Arzneim.-Forsch. 27, 5 ff. (1977)) erhalten werden durch Kondensation von Theophyllin mit entsprechenden Alkylendihalogeniden bzw. Epichlorhydrin. Die als Ausgangsstoffe diendenden Basen der Formel (III) sind ebenfalls als Handelsprodukte in Form ihrer Hydrochlorid-Salze erhältlich, aus denen sie vor Verwendung zur erfindungsgemässen Reaktion durch Behandlung beispielsweise mit Alkalimetallhydroxid auf dem Fachmann bekannte Weise freizusetzen sind.The starting materials of the formula (II) are known and the majority are commercially available; if desired, they can be obtained in a known manner (see Medic. Forsch. 27, 5 ff. (1977)) by condensation of theophylline with corresponding alkylene dihalides or epichlorohydrin. The bases of the formula (III) which are used as starting materials are likewise available as commercial products in the form of their hydrochloride salts, from which they are to be released in a manner known to the person skilled in the art before being used for the reaction according to the invention, for example by treatment with alkali metal hydroxide.

Es hat sich gezeigt, dass die erfindungsgemässen Theophyllinderivate überraschend vielseitige pharmakologische Wirkungen erkennen lassen.It has been shown that the theophylline derivatives according to the invention have surprisingly versatile pharmacological effects.

Die pharmakodynamischen Eigenschaften der Xanthinderivate haben den Anlass gegeben, dass auch das Theophyllin und seine Abkömmlinge von der pharmazeutischen Chemie wegen ihrer Herz-/Kreislaufwirkung intensiv bearbeitet worden sind. Schon zu Beginn des Jahrhunderts hat man begonnen, das Theophyllin-Molekül, um dem Nachteil seiner geringen Wasserlöslichkeit zu begegnen, mit basischen Gruppen zu substituieren, und in der Folge ist eine grosse Zahl von Theophyllinderivaten synthetisiert worden, teils mit hydrophilen Substituenten in 7-Stellung, teils auch in Form von Salzen und Additions- bzw. Doppelverbindungen. Viele derselben haben als Arzneisubstanzen in die Therapie Eingang gefunden, wobei man von ihrer günstigen Beeinflussung des Kreislaufes unmittelbaren oder mittelbaren Gebrauch gemacht hat, um sie als Vaso-, Coronar-, Bronchodilatatoren oder Antiasthmatica einzusetzen, soweit es sich nicht um Salze bzw. Doppel-Verbindungen oder dgl. handelt, deren hinzugekommene Ionen bzw. Molekülkomponenten (wie etwa im Falle des Ephedrins spezifische eigene pharmakologische Wirkungen aufweisen und in diesem Sinne zusätzliche Wirkungskomponenten hinzutreten lassen oder die Wirkung des Theophyllins sogar überschatten und dominieren.The pharmacodynamic properties of the xanthine derivatives have given rise to the fact that theophylline and its descendants have been intensively processed by pharmaceutical chemistry because of their cardiovascular effects. Already at the beginning of the century In order to counteract the disadvantage of its low water solubility, the theophylline molecule was started to be substituted with basic groups, and a large number of theophylline derivatives were subsequently synthesized, partly with hydrophilic substituents in the 7-position and partly also in the form of Salts and addition or double compounds. Many of these have found their way into therapy as medicinal substances, and direct or indirect use has been made of their favorable effects on the circulation in order to use them as vaso, coronary, bronchodilators or anti-asthmatics, insofar as they are not salts or double agents. Compounds or the like., Whose added ions or molecular components (such as in the case of ephedrine have specific pharmacological effects of their own and in this sense allow additional active components to be added or even overshadow and dominate the effect of theophylline.

Vor kurzem sind nun in DE-OS 29 22 159 7-(4-Aminopiperidino-propyl)-theophylline mit antiallergischer und Antihistamin-Wirkung beschrieben worden. In ähnliche Richtungen weisen auch erfindungsge.näss Substanzen, für welche u.a. markante histamin-, serotonin- und bradykininantagonistische, blutdrucksenkende, antianaphylaktische und β-adrenerg stimulierende Eigenschaften nachgewiesen wurden und die sich durch dieses breite Wirkungsspektrum von den herkömmlichen Theophyllinderivaten deutlich abheben. Aufgrund der genannten pharmakodynamischen Eigenschaften lassen sie sich für die therapeutische Verwendung als Migränemittel, Broncholytica, Antiallergica, Antiphlogistica, Analgetica und Antihypertonica einsetzen. Als besonders vielversprechend erwiesen sich die Substanzen mit der Code-Bezeichnung Sgd 195-78 (vgl. nachfolgendes Beispiel 2) und Sgd 144-80 (vgl. Beispiel 3). Demgemäss haben nach dem derzeitigen Stand der Kenntnis diejenigen Verbindungen der Formel (I) als bevorzugt zu gelten, bei denen R ein Wasserstoffatom, n die Zahl null oder eins (vorzugsweise null), X die Methylengruppe, Y die Ketogruppe und Ar einen parasubstituierten Phenylrest, insbesondere die p-Fluorphenylgruppe bedeutet.Recently, DE-OS 29 22 159 7- (4-aminopiperidino-propyl) theophylline with antiallergic and antihistamine effects have been described. Substances for which, among other things, Distinctive histamine, serotonin and bradykinin antagonistic, antihypertensive, antianaphylactic and β-adrenergic stimulating properties have been demonstrated and which stand out clearly from the conventional theophyllin derivatives due to this broad spectrum of activity. Due to the pharmacodynamic properties mentioned, they can be used for therapeutic use as migraine drugs, broncholytics, antiallergics, antiphlogistics, analgesics and antihypertonica. The substances with the code designation Sgd 195-78 (see Example 2 below) and Sgd 144-80 (see Example 3) proved to be particularly promising. Accordingly, according to the current state of knowledge, those compounds of the formula (I) are to be regarded as preferred in which R is a hydrogen atom, n is the number zero or one (preferably zero), X is the methylene group, Y is the keto group and Ar is a parasubstituted phenyl radical, in particular the p-fluorophenyl group.

Bei den Strukturformeln der nachfolgenden Beispiele bedeutet "Th" die Theophyllinylgruppe, die in 7-Position an die im jeweiligen Beispiel wiedergegebene Teilstruktur gebunden ist.In the structural formulas of the examples below, "Th" means the theophyllinyl group which is attached in the 7-position to the partial structure shown in the respective example.

B e i s p i e l 1Example 1 7-[2-[4-(p-Tolyloxy)-piperidino]-ethyl]-theophyllin (Sgd 94-78)7- [2- [4- (p-tolyloxy) piperidino] ethyl] theophylline (Sgd 94-78)

Figure imgb0006
2,4 g (0,01 Mol) 7-(2-Chlorethyl)-theophyllin werden mit 3,8 g (0,02 Mol) 4-(p-Tolyloxy)-piperidin in festem Zustand sorgfältig gemischt und in einem Rundkolben auf dem Oelbad bei einer Badtemperatur von 90°C erhitzt. Dabei bildet sich bald eine klare Schmelze, worauf sich das Gemisch nach ungefähr 15 Minuten wieder verfestigt. Die Masse wird weiterhin auf gleicher Temperatur gehalten, bis die Kontrolle durch Dünnschicht-Chromatographie (CHC13 + 10% Methanol) erkennen lässt, dass die Reaktion beendet ist. Dies ist nach ungefähr 6 Stunden der Fall. Dann lässt man erkalten, versetzt mit Wasser und extrahiert mit Chloroform. Nach Trocknen des Extraktes über MgS04 wird das Chloroform abdestilliert. Der Rückstand wird zweimal aus Isopropanol umkristallisiert und ergibt dabei 3,0 g Produkt mit Smp. 121 - 122°C.
Figure imgb0007
Figure imgb0006
 2.4 g (0.01 mol) of 7- (2-chloroethyl) theophylline are thoroughly mixed with 3.8 g (0.02 mol) of 4- (p-tolyloxy) piperidine in the solid state and placed in a round bottom flask heated the oil bath at a bath temperature of 90 ° C. A clear melt soon forms, after which the mixture solidifies again after about 15 minutes. The mass is kept at the same temperature until the control by thin layer chromatography (CHC1 3 + 10% methanol) shows that the reaction has ended. This is the case after about 6 hours. Then allowed to cool, mixed with water and extracted with chloroform. After drying the extract over MgS0 4 , the chloroform is distilled off. The residue is recrystallized twice from isopropanol and gives 3.0 g of product with mp. 121-122 ° C.
Figure imgb0007

Das als Ausgangsstoff benützte 7-(2-Chlorethyl)-theophyllin isL bekannt und durch Umsetzung von Theophyllin und Ethylendichlorid erhältlich. Das als freie Base eingesetzte 4-(p-Tolyloxy)-piperidin lässt sich aus dem entsprechenden Hydrochlorid durch Behandlung mit Natronlauge erhalten.The 7- (2-chloroethyl) theophylline used as starting material is known and can be obtained by reacting theophylline and ethylene dichloride. The 4- (p-tolyloxy) piperidine used as the free base can be obtained from the corresponding hydrochloride by treatment with sodium hydroxide solution.

B e i s p i e l 2Example: 2 7-[2-[4-(p-Fluorbenzoyl)-piperidiho]-ethyH-theophyllin (Sgd 195-78)7- [2- [4- (p-fluorobenzoyl) piperidiho] ethylH theophylline (Sgd 195-78)

Figure imgb0008
25,6 g (0,124 M) 4-(p-Fluorbenzoyl)-piperidin werden zusammen mit 15,0 g (0,062 M) 7-(2-Chlorethyl)-theophyllin in festem Zustand in einem Rundkolben während 1 Stunde auf 100°C erhitzt. Danach kühlt man auf 60°C und gibt unter Rühren Essigester zu, bis eine homogene Suspension vorliegt. Nach Abkühlen und Abfiltrieren des ausgeschiedenen Fluorbenzoylpiperidin-Hydrochlorids setzt man dem Filtrat zum Ausfällen des rohen Produktes 2n Salzsäure zu. Der durch Filtration abgetrennte Rückstand wird je zweimal mit Wasser und Essigester gewaschen, anschliessend mit Essigester überschichtet und mit 100 ml 2n Natronlauge versetzt. Nach Ausschütteln und Phasentrennung befindet sich die Hauptmenge des Produkts in der organischen Phase; zur Gewinnung weiterer Produktmengen wird die wässrige Phase zweimal mit je 100 ml Essigester ausgeschüttelt. Die vereinigten organischen Phasen werden mit gesättigter NaCl-Lösung gewaschen, mit Aktivkohle behandelt, über MgS04 getrocknet und filtriert. Aus dem Filtrat erhält man durch Abdestillieren des Lösungsmittels 20,4 g (80%) rohes kristallines Produkt. Zur weiteren Reinigung wird der Rückstand in 250 ml Tetrachlorkohlenstoff suspendiert und auf Rückflusstemperatur erhitzt. Die dabei entstehende dunkelbraune Lösung wird nach Behandlung mit Aktivkohle hellorange und liefert beim Abkühlen 14,5 g weisses Produkt mit Smp. 143 - 145°C, das sich im Dünnschicht-Chromatogramm als rein erweist.
Figure imgb0009
Figure imgb0008
 25.6 g (0.124 M) 4- (p-fluorobenzoyl) piperidine together with 15.0 g (0.062 M) 7- (2-chloroethyl) theophylline in the solid state in a round bottom flask at 100 ° C. for 1 hour heated. Then it is cooled to 60 ° C. and ethyl acetate is added with stirring until a homogeneous suspension is obtained. After cooling and filtering off the excreted fluorobenzoylpiperidine hydrochloride, 2N hydrochloric acid is added to the filtrate to precipitate the crude product. The residue separated off by filtration is washed twice with water and ethyl acetate, then covered with ethyl acetate and mixed with 100 ml of 2N sodium hydroxide solution. After shaking and phase separation, the majority of the product is in the organic phase; to obtain further amounts of product, the aqueous phase is shaken out twice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated NaCl solution, treated with activated carbon, dried over MgSO 4 and filtered. 20.4 g (80%) of crude crystalline product are obtained from the filtrate by distilling off the solvent. For further purification, the residue is suspended in 250 ml of carbon tetrachloride and heated to the reflux temperature. The resulting dark brown solution becomes light orange after treatment with activated carbon and supplies 14.5 g of white product with a melting point of 143-145 ° C, which turns out to be pure in the thin-layer chromatogram.
Figure imgb0009

Durch fünfstündiges Erhitzen der im gleichen Verhältnis gemischten Ausgangsstoffe auf 120°C, anschliessendes Kochen in n-Propanol während 7 Stunden, entsprechende Aufarbeitung und Kristallisieren aus Tetrachlorkohlenstoff wurde ein gemäss Dünnschicht-Chromatogramm reines Produkt gleicher Zusammensetzung erhalten, welches bei 248°C unter Zersetzung schmilzt.

Figure imgb0010
By heating the starting materials mixed in the same ratio to 120 ° C for five hours, then boiling in n-propanol for 7 hours, working up accordingly and crystallizing from carbon tetrachloride, a product of the same composition was obtained which was pure according to the thin-layer chromatogram and which melts at 248 ° C with decomposition .
Figure imgb0010

e e i s p i e l 3e e i s p i e l 3 7-[3-[4-(p-Fluorbenzoyl)-piperidino]-propyl]-theophyllin (Sgd 144-80)7- [3- [4- (p-fluorobenzoyl) piperidino] propyl] theophylline (Sgd 144-80)

Figure imgb0011
10,2 g 4-(p-Fluorbenzoyl)-piperidin und 16,5 g 7-(3-Chlorpropyl)-theophyllin werden in festem Zustand sorgfältig gemischt und in einem Rundkolben im Oelbad auf 100°C erhitzt. Das Gemisch ergibt dabei zunächst eine klare Schmelze, beginnt dann zu kristallisieren und verwandelt sich schliesslich in eine feste Masse. Nach 10 Minuten lässt man diese abkühlen, löst sie in Essigester auf und versetzt die Lösung mit 2n Salzsäure, wobei sich in der organischen Phase ein dunkles Oel abscheidet, das bei Stehenlassen Über Nacht durchkristallisiert. Durch Umkristallisieren aus 100 ml Tetrachlorkohlenstoff erhält man als zunächst wiederum ölige, später auskristallisierende Substanz 7,4 g Produkt mit Smp. 114 - 119°C (Ausbeute: 43,5%).
Figure imgb0012
Figure imgb0011
 10.2 g of 4- (p-fluorobenzoyl) piperidine and 16.5 g of 7- (3-chloropropyl) theophylline are carefully mixed in the solid state and heated to 100 ° C. in a round bottom flask in an oil bath. The mixture initially produces a clear melt, then begins to crystallize and finally transforms into a solid mass. After 10 minutes, the mixture is allowed to cool, dissolved in ethyl acetate, and 2N hydrochloric acid is added to the solution, a dark oil separating out in the organic phase, which crystallizes on standing overnight. By recrystallization from 100 ml of carbon tetrachloride, 7.4 g of product with mp 114-119 ° C. (yield: 43.5%) is obtained as an initially again oily substance which later crystallizes out.
Figure imgb0012

Das als Ausgangsprodukt benutzte 7-(3-Chlorpropyl)-theophyllin lässt sich auf bekannte Weise beispielsweise durch Umsetzung von Theophyllin mit 1,3-Bromchlorpropan erhalten.The 7- (3-chloropropyl) theophylline used as the starting product can be obtained in a known manner, for example by reacting theophylline with 1,3-bromochloropropane.

B e i s p i e l 4Example 4 7-[3-[4-(p-Fluorbenzoyl)-piperidino]-2-hydroxy-propyl]-theophyllin-Hydrat (Sgd 145-80)7- [3- [4- (p-fluorobenzoyl) piperidino] -2-hydroxypropyl] theophylline hydrate (Sgd 145-80)

Figure imgb0013
8 g 7-(3-Chlor-2-hydroxy-propyl)-theophyllin in Mischung mit 12.16 g 4-(p-Fluorbenzoyl)-piperidin werden im Oelbad während 1 Stunde auf einer Temperatur von 100°C gehalten, wobei die Viscosität der anfänglich dünnflüssigen, klaren Schmelze nach etwa 30 Min. zunehmend ansteigt. Nach Abkühlung wird das Gemisch unter intensivem Rühren während 30 Min. mit Essigester behandelt. Die entstandene Lösung wird durch Filtrieren vom ausgeschiedenen 4-(p-Fluorbenzoyl)-piperidin-Hydrochlorid abgetrennt und mit 2n Salzsäure versetzt. Nach Phasentrennung wird die wässrige Phase nach zweimaligem Ausschütteln mit Essigester durch Zugabe von konzentrierter Natronlauge alkalisch gestellt und zweimal mit Essigester extrahiert. Die aus dem Extrakt auskristallisierende Substanz zeigt nach Umkristallisieren aus Chloroform + Ethanol (9:1) und Trocknen im Hochvakuum einen Schmelzpunkt von 132 - 138°C.
Figure imgb0014
Figure imgb0013
 8 g of 7- (3-chloro-2-hydroxypropyl) theophylline in a mixture with 12.16 g of 4- (p-fluorobenzoyl) piperidine are kept in an oil bath at a temperature of 100 ° C. for 1 hour, the viscosity of the initially thin, clear melt gradually increases after about 30 minutes. After cooling, the mixture is treated with ethyl acetate with intensive stirring for 30 minutes. The resulting solution is separated from the separated 4- (p-fluorobenzoyl) piperidine hydrochloride by filtration and mixed with 2N hydrochloric acid. After phase separation, after shaking twice with ethyl acetate, the aqueous phase is made alkaline by adding concentrated sodium hydroxide solution and extracted twice with ethyl acetate. After recrystallization from chloroform + ethanol (9: 1) and drying in a high vacuum, the substance which crystallizes from the extract shows a melting point of 132-138 ° C.
Figure imgb0014

Das als Ausgangsmaterial benützte 7-(3-Chlor-2-hydroxy-propyl)-theophyllin lässt sich auf bekannte Weise durch Reaktion von Theophyllin mit Epichlorhydrin erhalten.The 7- (3-chloro-2-hydroxypropyl) theophylline used as the starting material can be obtained in a known manner by reacting theophylline with epichlorohydrin.

B e i s p i e l 5Example 5 7-[3-[4-(2-furoyl)-1-piperazinyl]-2-hydroxy-propyl]-theophyllin (Sgd 269-76)7- [3- [4- (2-furoyl) -1-piperazinyl] -2-hydroxypropyl] theophylline (Sgd 269-76)

Figure imgb0015
Ein Gemisch von 2 g (8,26 mMol) 7-(2-Chloraethyl)-theophyllin und 3,78 g (21 mMol) N-Furoylpiperazin wird auf dem Oelbad bei 100°C geschmolzen und 3 Stunden auf dieser Temperatur gehalten. Nach Abkühlen wird die erstarrte Masse in Methylenchlorid aufgelöst. Die Lösung wird mit Wasser extrahiert und anschliessend zweimal mit Salzsäure (10%) durchgeschüttelt. Die vereinigten wässrigen Phasen werden mit Natronlauge alkalisch gestellt und wiederum mit Methylenchlorid extrahiert, und der so erhaltene Extrakt wird über Mg SO4 getrocknet und eingeengt. Der Rückstand wird zweimal mit Wasser bei 60°C gewaschen und wieder in Methylenchlorid gelöst. Aus der Lösung erhält man nach Trocknung über MgS04, Abdampfen des Lösungsmittels und Umkristallisieren aus Essigester das reine Produkt mit Smp. 142 - 144°C.
Figure imgb0016
Figure imgb0015
 A mixture of 2 g (8.26 mmol) of 7- (2-chloroethyl) theophylline and 3.78 g (21 mmol) of N-furoylpiperazine is melted on the oil bath at 100 ° C. and kept at this temperature for 3 hours. After cooling, the solidified mass is dissolved in methylene chloride. The solution is extracted with water and then shaken twice with hydrochloric acid (10%). The combined aqueous phases are made alkaline with sodium hydroxide solution and extracted again with methylene chloride, and the extract thus obtained is dried over MgSO 4 and concentrated. The residue is washed twice with water at 60 ° C and redissolved in methylene chloride. After drying over MgSO 4 , evaporation of the solvent and recrystallization from ethyl acetate, the pure product with mp 142-144 ° C. is obtained from the solution.
Figure imgb0016

B e i s p i e l 6Example 6 7-[3-[4-(2-Furoyl)-1-piperazinyl]-2-hydroxy-propyl]-theophyllin (Sgd 123-77)7- [3- [4- (2-Furoyl) -1-piperazinyl] -2-hydroxypropyl] theophylline (Sgd 123-77)

Figure imgb0017
Figure imgb0017

Eine Mischung von 4 g 7-(3-Chlor-2-hydroxy-propyl)-theophyllin mit 6,6 g N-(2-Furoyl)-piperazin wird 1 Stunde auf 120°C erhitzt; das Reaktionsgemisch wird in Chloroform gelöst und mit Wasser extrahiert. Die organische Phase wird über MgS04 getrocknet und eingeengt. Der Rückstand ergibt nach Umkristallisieren aus Isopropanol 2,8 g Produkt mit Smp. 161 - 163°C.

Figure imgb0018
A mixture of 4 g of 7- (3-chloro-2-hydroxypropyl) theophylline with 6.6 g of N- (2-furoyl) piperazine is heated to 120 ° C. for 1 hour; the reaction mixture is dissolved in chloroform and extracted with water. The organic phase is dried over MgS0 4 and concentrated. After recrystallization from isopropanol, the residue gives 2.8 g of product with mp. 161-163 ° C.
Figure imgb0018

Claims (4)

1. Theophyllinderivate der Formel
Figure imgb0019
und ihrer Salze mit pharmazeutisch zulässigen Säuren, wobei R Wasserstoff oder die Hydroxygruppe n die Zahlen null oder eins x
Figure imgb0020
 Y -0- oder
Figure imgb0021
und Ar einen gegebenenfalls mit Niederalkyl oder Nideralkoxy mit 1 bis 3 C-Atomen, mit Halogen oder mit Halogenmethyl substituierten fünf- oder sechsgliedrigen carbocyclischen oder heterocyclischen aromatisch ungesättigten Ring bedeuten. 1. Theophyllin derivatives of the formula
Figure imgb0019
 and their salts with pharmaceutically acceptable acids, whereby R is hydrogen or the hydroxy group n the numbers zero or one x
Figure imgb0020
 Y -0- or
Figure imgb0021
 and Ar is a five- or six-membered carbocyclic or heterocyclic aromatic-unsaturated ring which is optionally substituted with lower alkyl or lower alkoxy having 1 to 3 carbon atoms, with halogen or with halogenomethyl. 2. Verfahren zur Herstellung von Theophyllinderivaten der Formel I von Anspruch 1, dadurch gekennzeichnet dass man in 7-Stellung mit einer Gruppe der Formel
Figure imgb0022
substituiertes Theophyllin (wobei R und n die oben genannte Bedeutung haben und "Hal" Chlor oder Brom bedeutet) mit einer Base der Formel
Figure imgb0023
zur Reaktion bringt.2. A process for the preparation of theophyllin derivatives of the formula I of claim 1, characterized in that in the 7-position with a group of the formula
Figure imgb0022
 substituted theophylline (where R and n are Be have meaning and "Hal" means chlorine or bromine) with a base of the formula
Figure imgb0023
 to react. 3. Theophyllinderivate nach Anspruch 1, dadurch gekennzeichnet, dass R ein Wasserstoffatom, n null oder eins, X die Methylengruppe, Y die Ketogruppe und Ar die p- Fluorphenylgruppe bedeutet.3. Theophyllinderivate according to claim 1, characterized in that R is a hydrogen atom, n is zero or one, X is the methylene group, Y is the keto group and Ar is the p- F luorphenyl group. 4. 7-[2-[4-(p-Fluorbenzoyl)-piperidino]-ethyl]-theophyllin.4. 7- [2- [4- (p-fluorobenzoyl) piperidino] ethyl] theophylline.
EP82105665A 1981-07-20 1982-06-25 Theophylline derivatives and process for their preparation Expired EP0071738B1 (en)

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EP0087810A1 (en) * 1982-03-02 1983-09-07 Eisai Co., Ltd. Antiphlogistic/antipyretic/analgesic pharmaceutical compositions containing theophylline derivatives as active ingredient
EP0177087A2 (en) * 1984-10-01 1986-04-09 Janssen Pharmaceutica N.V. 1H-Indol-3-yl containing 1,3-dimethyl-1H-purine-2,6-diones
EP0229897A1 (en) * 1985-12-26 1987-07-29 Siegfried Aktiengesellschaft Alpha1-adrenergic-blocking theophylline derivatives
EP0261688A1 (en) * 1986-09-26 1988-03-30 Sumitomo Pharmaceuticals Company, Limited Imide derivatives, and their production and use
EP0271192A2 (en) * 1986-10-21 1988-06-15 American Home Products Corporation Purine histamine H1 antagonists, their preparation and pharmaceutical compositions containing them
EP0307014A1 (en) * 1987-07-10 1989-03-15 Janssen Pharmaceutica N.V. Anti-allergic 2-(heterocyclyl alkyl) imidazo pyridines and 2-(heterocyclyl alkyl) purines
FR2812290A1 (en) * 2000-07-28 2002-02-01 Ing Jun Chen New 3-alkyl-7-(2-(amino or piperazino)-ethyl)-1-methyl-xanthine derivatives, are phosphodiesterase V inhibitors useful for relaxing the corpus cavernosum

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CH648559A5 (en) * 1981-07-20 1985-03-29 Siegfried Ag THEOPHYLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF.
JPS6063658U (en) * 1983-10-07 1985-05-04 日本フレツクス工業株式会社 Hook device separation release mechanism
FR2558162B1 (en) * 1984-01-17 1986-04-25 Adir NOVEL XANTHINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JPH0615529B2 (en) * 1985-04-01 1994-03-02 エーザイ株式会社 Novel piperidine derivative
US4810706A (en) * 1985-12-20 1989-03-07 Recherche Syntex Piperazine derivatives of theophylline and theobromine
US4716165A (en) * 1986-09-24 1987-12-29 American Home Products Corporation Histamine H1 antagonists
US4716166A (en) * 1986-10-21 1987-12-29 American Home Products Corporation Histamine H1 antagonists
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US5641783A (en) * 1993-11-12 1997-06-24 Cell Therapeutics, Inc. Substituted amino alcohol compounds
US5837703A (en) * 1993-03-31 1998-11-17 Cell Therapeutics, Inc. Amino-alcohol substituted cyclic compounds
JP3850480B2 (en) * 1996-01-29 2006-11-29 中央発條株式会社 Remote control device using cable
RU2333212C3 (en) * 2007-03-29 2019-08-26 Общество С Ограниченной Ответственностью "Фармвинг" 1- AND 7- [ω- (BENZHYDRIL-4-PIPERAZINYL-1) ALKYL] -3-ALKYLXANTINE DERIVATIVES PREVENTING ANTI-HISTAMIN AND ANTIALLERGIC ACTIVITY
HUE031039T2 (en) * 2007-03-29 2017-06-28 Joint-Stock Company Obninsk Chemical Pharmaceutical Company Antihistaminic and antiallergic agent and a method for the production thereof.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0087810A1 (en) * 1982-03-02 1983-09-07 Eisai Co., Ltd. Antiphlogistic/antipyretic/analgesic pharmaceutical compositions containing theophylline derivatives as active ingredient
EP0177087A2 (en) * 1984-10-01 1986-04-09 Janssen Pharmaceutica N.V. 1H-Indol-3-yl containing 1,3-dimethyl-1H-purine-2,6-diones
EP0177087A3 (en) * 1984-10-01 1986-06-11 Janssen Pharmaceutica N.V. 1h-indol-3-yl containing 1,3-dimethyl-1h-purine-2,6-diones
EP0229897A1 (en) * 1985-12-26 1987-07-29 Siegfried Aktiengesellschaft Alpha1-adrenergic-blocking theophylline derivatives
EP0261688A1 (en) * 1986-09-26 1988-03-30 Sumitomo Pharmaceuticals Company, Limited Imide derivatives, and their production and use
EP0271192A2 (en) * 1986-10-21 1988-06-15 American Home Products Corporation Purine histamine H1 antagonists, their preparation and pharmaceutical compositions containing them
EP0271192A3 (en) * 1986-10-21 1988-06-29 American Home Products Corporation Purine histamine h1 antagonists, their preparation and pharmaceutical compositions containing them
EP0307014A1 (en) * 1987-07-10 1989-03-15 Janssen Pharmaceutica N.V. Anti-allergic 2-(heterocyclyl alkyl) imidazo pyridines and 2-(heterocyclyl alkyl) purines
FR2812290A1 (en) * 2000-07-28 2002-02-01 Ing Jun Chen New 3-alkyl-7-(2-(amino or piperazino)-ethyl)-1-methyl-xanthine derivatives, are phosphodiesterase V inhibitors useful for relaxing the corpus cavernosum

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